[14C]acetylcholine synthesis and [14C]carbon dioxide production from [U-14C]glucose by tissue prisms from human neocortex.
1. [14C]Acetylcholine synthesis and 14CO2 production from [U-14C]glucose has been measured in tissue prism preparations from human neocortex. 2. Electron micrographs of prisms from human and rat neocortex show that both contain intact synaptic endings with evenly-distributed vesicles and normal-appearing mitochondria, but only poorly preserved cell body structure. 3. Synthesis of [14C]acetylcholine in prisms from rat neocortex is similar to estimates for turnover in vivo. Synthesis in prisms from human neocortex is 18% of that in rat tissue and 64% of that in tissue from baboon neocortex for incubations performed in 31 mM-K+. 4. Investigations of prisms prepared from rat brains stored at 37 degrees C after death revealed that synthesis of [14C]acetylcholine in the presence of 31 mM-K+ was greatly decreased within 30 min of post-mortem incubation, whereas synthesis at 5 mM-K+ and production of 14CO2 at both K+ concentrations were only significantly affected after longer periods. Changes were similar in neocortex and striatum. Thus human autopsy material is unlikely to be suitable for use with this system. 5. Investigations using animal models suggest that [14C]acetylcholine synthesis and 14CO2 production are not affected by surgical or anaesthetic procedures. 6. Neither [14C]acetylcholine synthesis nor 14CO2 production in human prisms was significantly changed with age between 15 and 68 years. 7. Samples from patients with the dementing condition Alzheimer's disease showed a significant decrease in [14C]acetylcholine synthesis to 47% of normal samples and a significant increase of 39% in production of 14CO2.


A rare thymoma type presenting as a giant intrathoracic tumor: lipofibroadenoma.
Type B1 thymoma (lipofibroadenoma) is extremely rare. The tumor is characterized by an organoid appearance rich in lymphocytes with medullary differentiation and perivascular spaces. A twenty-three-year-old female patient was admitted to our clinic with complaints of chest pain and dyspnea for six months. Chest computed tomography showed solid and fatty components of masses 21×7 and 5×7 cm with clear borders in the right thoracic cavity. The patient underwent a posterolateral thoracotomy in which the mass, arising from the anterior mediastinum, was resected. Histopathological examination showed that the mass was Type B1 thymoma, and the patient was presented in light of the literature.


Evaluation of Opioid Prescribing Habits Based on Analysis of a State Prescription Drug Monitoring Program.
The current opioid epidemic is perhaps the greatest public health crisis in the United States. Although multiple factors led to the rise of this epidemic, it is without question associated with the rise in opioid prescribing. Better understanding of the opioid prescribing may provide insights into population-level trends contributing to this epidemic, and opportunities to decrease the magnitude of opioid overdose-related death. Therefore we assessed trends in opioid prescribing habits based on analysis of the Texas Prescription Drug Monitoring Program (PDMP) and geographic, ethnic, and income-related data from the US Census Bureau. Multiple linear regression analysis of Texas PDMP and US Census Bureau data were performed to assess for correlations to opioid prescribing based on geographic, ethnic, income, and time-related variables. All controlled substances prescribed in the state of Texas from April 2015 to May 2018 were analyzed. We obtained data from the Texas PDMP for all controlled substances from April 2015 to May 2018. We performed multiple linear regression analysis of these data along with US Census Bureau data to assess for correlations based on geographic, ethnic, income, and time-related variables. We hypothesized that there would be substantial variability in opioid prescribing habits based on geographic, ethnic, and economic variables. Approximately 200 million pills of controlled substances were prescribed per month over the studied time frame. Overall, high geographic variability was noted, and this strongly correlated to race and ethnicity. Opioid prescribing increased along with the proportion of white residents within a county, but a similar negative correlation was noted with increasing Hispanic population proportion. This correlation was noted throughout the study period, but up until 2017, lower income levels among higher white population had even higher correlation with increased opioid prescribing. Cumulative opioid prescriptions throughout the state fell beginning in 2017. This analysis does not include opioids obtained illicitly or from prescriptions outside the state of Texas. The specificity of geographic data are limited to the county level due to irregular entry of zip code data by prescribing pharmacies. In the state of Texas over the studied time period, there was strong correlation for higher rates of opioid prescribing as white population increased despite overall decreased opioid prescribing starting in 2017. Until 2017, this correlation grew stronger as low-income white population increased. Opioid, opioid epidemic, opioid utilization.


Catecholaminergic modulation of the avoidance of cognitive control.
The catecholamines have long been associated with cognitive control and value-based decision-making. More recently, we proposed that the catecholamines might modulate value-based decision-making about whether or not to engage in cognitive control. We test this hypothesis by assessing effects of a catecholamine challenge in a large sample of young, healthy adults (n = 100) on the avoidance of a cognitively demanding control process: task switching. Prolonging catecholamine transmission by blocking reuptake with methylphenidate altered the avoidance, but not the execution of cognitive control. Crucially, these effects could be isolated by taking into account individual differences in trait impulsivity, so that participants with higher trait impulsivity became more avoidant of cognitive control, despite faster task performance. One implication of these findings is that performance-enhancing effects of methylphenidate may be accompanied by an undermining effect on the willingness to exert cognitive control. Taken together, these findings integrate hitherto segregated literatures on catecholamines' roles in value-based learning/choice and cognitive control. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Circadian variations of epithelial cell proliferation in human rectal crypts.
Evidence (almost exclusively from animal studies) suggests that proliferation within the colorectal mucosa undergoes circadian variations. The epithelial cells that line the human colorectal crypt occupy definite positions along the longitudinal axis according to their proliferative potential and degree of differentiation. Thus, circadian rhythmicity was investigated in humans to locate the areas along the longitudinal crypt axis in which diurnal fluctuation might occur. Rectal mucosal biopsy specimens were obtained every 4 hours for a 24-hour span from each of 23 subjects (8 healthy volunteers and 15 with histories of sporadic adenomatous polyps). [3H]thymidine histoautoradiography was used to determine ratios of S-phase to total cells (total labeling index) in the crypt. Glands were also divided into 5 equal compartments from base (compartment 1) to mouth (compartment 5), and labeling indices were calculated for each. Important temporal variations were confined to compartment 2 (F = 5.15, P = 0.0003) and total labeling indices (F = 3.57, P = 0.005). Despite individual variations, proliferation was generally higher at night and lower during afternoon. Upper-crypt proliferative rates (compartments 4 and 5) remained decidedly stable (F = 0.5, P = NS). Normal subjects and patients with polyps displayed similar circadian behaviors. Circadian fluctuation in proliferation is confined to the area of the crypt normally associated with replication. Upper-crypt indices, including those that were higher than normal (a colon-cancer risk marker) are stable over 24 hours. These findings should be useful in planning chemoprevention trials and chemotherapeutic regimens.


Influences of rurality on action to diagnose cancer by primary care practitioners - Results from a Europe-wide survey in 20 countries.
Rural-dwellers have poorer cancer outcomes than urban counterparts, for reasons which are unclear. At healthcare institution level, poorer access to investigations and different clinical decision-making by rural primary healthcare practitioners (PCPs) could be important. To compare access to investigations, attitudes to cancer diagnosis and clinical decision-making between rural and urban PCPs. A vignette-based cross-sectional survey of rural and urban PCPs in 20 European countries. Data on PCPs' decision-making and attitudes to cancer diagnosis were based on clinical scenarios. Comparisons were made using tests of proportion, univariable and multivariable binary logistic regression. Of the 1779 PCPs completing the survey 541 30.4 %) practiced rurally. Rural PCPs had significantly less direct access to all investigative modalities: ultrasound; endoscopy; x-ray and advanced screening (all p < 0.001). Rural PCPs were as likely as urban PCPs to take diagnostic action (investigation and/or referral) at the index consultation in all four clinical vignettes ((OR, 95 % CI) for lung: 0.90, 0.72-1.12; ovarian: 0.95, 0.75-1.19; breast: 0.87, 0.69-1.09; colorectal: 0.98, 0.75-1.30). Rural PCPs were less likely to refer to a specialist at the index consultation for ovarian cancer (OR 0.71 95 % CI 0.51-0.99). Rural PCPs were significantly more likely to report that their patients faced barriers to accessing specialist care, but practitioners did not report greater difficulties making specialist referral than their urban counterparts CONCLUSIONS: European rural PCPs report poorer access to investigations but are at least as likely as urban PCPs to investigate or refer patients that might have cancer at the index consultation.


Human metapneumovirus inhibits IFN-β signaling by downregulating Jak1 and Tyk2 cellular levels.
Human metapneumovirus (hMPV), a leading cause of respiratory tract infections in infants, inhibits type I interferon (IFN) signaling by an unidentified mechanism. In this study, we showed that infection of airway epithelial cells with hMPV decreased cellular level of Janus tyrosine kinase (Jak1) and tyrosine kinase 2 (Tyk2), due to enhanced proteosomal degradation and reduced gene transcription. In addition, hMPV infection also reduced the surface expression of type I IFN receptor (IFNAR). These inhibitory mechanisms are different from the ones employed by respiratory syncytial virus (RSV), which does not affect Jak1, Tyk2 or IFNAR expression, but degrades downstream signal transducer and activator of transcription proteins 2 (STAT2), although both viruses are pneumoviruses belonging to the Paramyxoviridae family. Our study identifies a novel mechanism by which hMPV inhibits STAT1 and 2 activation, ultimately leading to viral evasion of host IFN responses.


Effect of gliadin on permeability of intestinal biopsy explants from celiac disease patients and patients with non-celiac gluten sensitivity.
Intestinal exposure to gliadin leads to zonulin upregulation and consequent disassembly of intercellular tight junctions and increased intestinal permeability. We aimed to study response to gliadin exposure, in terms of barrier function and cytokine secretion, using intestinal biopsies obtained from four groups: celiac patients with active disease (ACD), celiac patients in remission (RCD), non-celiac patients with gluten sensitivity (GS) and non-celiac controls (NC). Ex-vivo human duodenal biopsies were mounted in microsnapwells and luminally incubated with either gliadin or media alone. Changes in transepithelial electrical resistance were monitored over 120 min. Media was subsequently collected and cytokines quantified. Intestinal explants from all groups (ACD (n = 6), RCD (n = 6), GS (n = 6), and NC (n = 5)) demonstrated a greater increase in permeability when exposed to gliadin vs. media alone. The increase in permeability in the ACD group was greater than in the RCD and NC groups. There was a greater increase in permeability in the GS group compared to the RCD group. There was no difference in permeability between the ACD and GS groups, between the RCD and NC groups, or between the NC and GS groups. IL-10 was significantly greater in the media of the NC group compared to the RCD and GS groups. Increased intestinal permeability after gliadin exposure occurs in all individuals. Following gliadin exposure, both patients with gluten sensitivity and those with active celiac disease demonstrate a greater increase in intestinal permeability than celiacs in disease remission. A higher concentration of IL-10 was measured in the media exposed to control explants compared to celiac disease in remission or gluten sensitivity.


Targeting carbon nanotubes against cancer.
The use of carbon nanotubes (CNTs) as polyvalent tools for cancer treatment is progressing at a very fast pace. The most promising approach is the targeted delivery of drugs, designed to selectively direct the therapeutic treatment towards the tumours. CNTs may offer several advantages to overcome one of the main limitations of most existing anticancer therapies, namely the lack of selectivity. Herein, an account of the existing literature on CNT-based nanomedicine for cancer treatment is given. The most significant results obtained so far in the field of drug delivery are presented for many anticancer chemotherapeutics (doxorubicin, methotrexate, taxanes, platinum analogues, camptothecine and gemcitabine), but also for immunotherapeutics and nucleic acids. Moreover, the alternative anticancer therapies based on thermal ablation and radiotherapy are discussed. The attention throughout the review is focused on the different targeting strategies proposed so far, mainly based on antibodies, but also on other specifically recognised molecules or on the application of an external magnetic field.


Non invasive analysis of miniature paintings: proposal for an analytical protocol.
The characterisation of palettes used in manuscript illumination is a hard analytical task, due to value and fragility of the analysed items. Analysis on miniatures must be necessarily non-invasive and fast and requires the use of several techniques since no single technique is able to provide all information needed. In this work a four-step analytical protocol is proposed for non-invasive in situ characterisation of miniature paintings. The protocol allows the identification of coloured materials through the use in sequence of complementary techniques, so as to fully exploit the information given by each instrument. Preliminarily to the instrumental investigations on ancient books and miniatures is the compilation of spectroscopic databases obtained from "standard" samples prepared on parchment, according to recipes described in medieval artistic treatises. The protocol starts with an extensive investigation with UV-visible spectrophotometry in reflectance mode, collecting spectra from all the most significant painted areas in the manuscript; chemometric classification is then performed on the spectra to highlight areas possibly containing the same materials. The second step involves in-depth inspection of miniatures under optical microscopy that guides the interpretation of reflectance spectra. XRF spectrometry is then performed to characterise pigments and metal layers, to verify the presence of overlapping layers, to identify mordants in lakes and to recognise minor components that may yield information concerning provenance; in addition, chemometric classification can be performed on element concentrations to highlight similar areas. Finally, Raman spectroscopy is used to shed light on the uncertain cases, if still present. Such a procedure offers a wealth of information without causing stress to the manuscripts under analysis.


A Deep Learning Approach to Visualize Aortic Aneurysm Morphology Without the Use of Intravenous Contrast Agents.
Intravenous contrast agents are routinely used in CT imaging to enable the visualization of intravascular pathology, such as with abdominal aortic aneurysms. However, the injection is contraindicated in patients with iodine allergy and is associated with renal complications. In this study, we investigate if the raw data acquired from a noncontrast CT image contains sufficient information to differentiate blood and other soft tissue components. A deep learning pipeline underpinned by generative adversarial networks was developed to simulate contrast enhanced CTA images using noncontrast CTs. Two generative models (cycle- and conditional) are trained with paired noncontrast and contrast enhanced CTs from seventy-five patients (total of 11,243 pairs of images) with abdominal aortic aneurysms in a 3-fold cross-validation approach with a training/testing split of 50:25 patients. Subsequently, models were evaluated on an independent validation cohort of 200 patients (total of 29,468 pairs of images). Both deep learning generative models are able to perform this image transformation task with the Cycle-generative adversarial network (GAN) model outperforming the Conditional-GAN model as measured by aneurysm lumen segmentation accuracy (Cycle-GAN: 86.1% ± 12.2% vs Con-GAN: 85.7% ± 10.4%) and thrombus spatial morphology classification accuracy (Cycle-GAN: 93.5% vs Con-GAN: 85.7%). This pipeline implements deep learning methods to generate CTAs from noncontrast images, without the need of contrast injection, that bear strong concordance to the ground truth and enable the assessment ofimportant clinical metrics. Our pipeline is poised to disrupt clinical pathways requiring intravenous contrast.


Myeloid Cell Nuclear Differentiation Antigen (MNDA) Expression Distinguishes Extramedullary Presentations of Myeloid Leukemia From Blastic Plasmacytoid Dendritic Cell Neoplasm.
Myeloid neoplasms constitute one of the most common malignancies in adults. In most cases these proliferations initially manifest in the blood and marrow; however, extramedullary involvement may precede blood or marrow involvement in a subset of cases, making a definitive diagnosis challenging by morphologic and immunohistochemical assessment alone. Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive entity that frequently presents in extramedullary sites and can show morphologic and immunophenotypic overlap with myeloid neoplasms. Given that BPDCN and myeloid neoplasms may both initially present in extramedullary sites and that novel targeted therapies may be developed that exploit the unique molecular signature of BPDCN, new immunophenotypic markers that can reliably separate myeloid neoplasms from BPDCN are desirable. We evaluated the utility of myeloid cell nuclear differentiation antigen (MNDA) expression in a series of extramedullary myeloid leukemias (EMLs) and BPDCN. Forty biopsies containing EML and 19 biopsies containing BPDCN were studied by MNDA immunohistochemistry. The majority of myeloid neoplasms showed nuclear expression of MNDA (65%). In contrast, all cases of BPDCN lacked MNDA expression. These findings show that MNDA is expressed in the majority of EMLs and support the inclusion of MNDA immunohistochemistry in the diagnostic evaluation of blastic hematopoietic infiltrates, particularly when the differential diagnosis is between myeloid leukemia and BPDCN.


Structural implications of drug-resistant mutants of HIV-1 protease: high-resolution crystal structures of the mutant protease/substrate analogue complexes.
Emergence of drug-resistant mutants of HIV-1 protease is an ongoing problem in the fight against AIDS. The mechanisms governing resistance are both complex and varied. We have determined crystal structures of HIV-1 protease mutants, D30N, K45I, N88D, and L90M complexed with peptide inhibitor analogues of CA-p2 and p2-NC cleavage sites in the Gag-pol precursor in order to study the structural mechanisms underlying resistance. The structures were determined at 1.55-1.9-A resolution and compared with the wild-type structure. The conformational disorder seen for most of the hydrophobic side-chains around the inhibitor binding site indicates flexibility of binding. Eight water molecules are conserved in all 9 structures; their location suggests that they are important for catalysis as well as structural stability. Structural differences among the mutants were analyzed in relation to the observed changes in protease activity and stability. Mutant L90M shows steric contacts with the catalytic Asp25 that could destabilize the catalytic loop at the dimer interface, leading to its observed decreased dimer stability and activity. Mutant K45I reduces the mobility of the flap and the inhibitor and contributes to an enhancement in structural stability and activity. The side-chain variations at residue 30 relative to wild-type are the largest in D30N and the changes are consistent with the altered activity observed with peptide substrates. Polar interactions in D30N are maintained, in agreement with the observed urea sensitivity. The side-chains of D30N and N88D are linked through a water molecule suggesting correlated changes at the two sites, as seen with clinical inhibitors. Structural changes seen in N88D are small; however, water molecules that mediate interactions between Asn88 and Thr74/Thr31/Asp30 in other complexes are missing in N88D.


Microbial contamination potential of sterile disposable plastic syringes.
The contamination potential of sterile disposable plastic syringes was evaluated after subjecting the syringes to both simulated in-use conditions and an intentional microbial challenge. Lots of 20 Luer-lock syringes in 10 or 12-cu cm and 20- or 30-cu cm sizes from three manufacturers were tested. Sampling was conducted using 30-ml vials of sterile aerobic culture media containing 14C-labeled substrates. Microbial contamination was confirmed by both visual observation of the turbidity caused by colonization and instrumental detection of 14CO2 caused by the microbial metabolism of 14C-substrates. No contamination of 120 samples was found after the ribbed plunger shaft was grasped by a bare, unprepared dry hand during five cycles of filling and injecting the medium into the vials without removing the needles from the stoppers. When this sampling technique was applied to the syringes inoculated on the upper piston surface with Bacillus subtilis suspension, a 100% contamination rate was observed in 120 samples each under both positive and negative in-vial pressure. Grasping the ribbed plunger shaft of disposable plastic syringes with a dry bare hand did not compromise the sterility of the syringe contents in this study; however, this practice should be avoided when possible. Personnel should absolutely avoid introducing fluid-borne microbial contaminants into the distal barrel end of these syringes because the contents are readily labile to contamination under these conditions.


High-resolution record reveals climate-driven environmental and sedimentary changes in an active rift.
Young rifts are shaped by combined tectonic and surface processes and climate, yet few records exist to evaluate the interplay of these processes over an extended period of early rift-basin development. Here, we present the longest and highest resolution record of sediment flux and paleoenvironmental changes when a young rift connects to the global oceans. New results from International Ocean Discovery Program (IODP) Expedition 381 in the Corinth Rift show 10s-100s of kyr cyclic variations in basin paleoenvironment as eustatic sea level fluctuated with respect to sills bounding this semi-isolated basin, and reveal substantial corresponding changes in the volume and character of sediment delivered into the rift. During interglacials, when the basin was marine, sedimentation rates were lower (excepting the Holocene), and bioturbation and organic carbon concentration higher. During glacials, the basin was isolated from the ocean, and sedimentation rates were higher (~2-7 times those in interglacials). We infer that reduced vegetation cover during glacials drove higher sediment flux from the rift flanks. These orbital-timescale changes in rate and type of basin infill will likely influence early rift sedimentary and faulting processes, potentially including syn-rift stratigraphy, sediment burial rates, and organic carbon flux and preservation on deep continental margins worldwide.


Neural self-representation in autistic women and association with 'compensatory camouflaging'.
Prior work has revealed sex/gender-dependent autistic characteristics across behavioural and neural/biological domains. It remains unclear whether and how neural sex/gender differences are related to behavioural sex/gender differences in autism. Here, we examined whether atypical neural responses during mentalizing and self-representation are sex/gender-dependent in autistic adults and explored whether 'camouflaging' (acting as if behaviourally neurotypical) is associated with sex/gender-dependent neural responses. In total, N = 119 adults (33 typically developing males, 29 autistic males, 29 typically developing females and 28 autistic females) participated in a task-related functional magnetic resonance imaging paradigm to assess neural activation within right temporo-parietal junction and ventromedial prefrontal cortex during mentalizing and self-representation. Camouflaging in autism was quantified as the discrepancy between extrinsic behaviour in social-interpersonal contexts and intrinsic status. While autistic men showed hypoactive right temporo-parietal junction mentalizing and ventromedial prefrontal cortex self-representation responses compared to typically developing men, such neural responses in autistic women were not different from typically developing women. In autistic women only, increasing camouflaging was associated with heightened ventromedial prefrontal cortex self-representation response. There is a lack of impaired neural self-representation and mentalizing in autistic women compared to typically developing women. Camouflaging is heightened in autistic women and may relate to neural self-representation response. These results reveal brain-behaviour relations that help explain sex/gender-heterogeneity in social brain function in autism.


[Antipsychotic drugs and cardiovascular safety: current studies of prolonged QT interval and risk of ventricular arrhythmia].
Cardiovascular mortality is higher among schizophrenic patients than in the general population, and it is possible that most unexplained sudden deaths among these patients are due to ventricular arrhythmias for which antipsychotic drugs are either the cause or a predisposing factor. Most antipsychotic agents show electrophysiological effects resembling those of class 1a antiarrhythmic agents, and may be responsible for prolonging the QT interval, potentially going on to cause torsades de pointes. Some of the antipsychotic agents carry a high risk of arrhythmias, related to their effects on the QT interval. These include thioridazine, pimozide, sultopride, droperidol, and to a lesser extent haloperidol and chlorpromazine. In the case of the new atypical antipsychotic agents, it is possible to rank the risks of different drugs, with sertindole (now withdrawn from sale) having the highest risk, and ziprasidone somewhat lower, followed by risperidone and finally by quetiapine, clozapine and olanzapine which have negligible effects on the QT interval. A number of risk factors have been demonstrated, particularly: hypokalaemia and hypomagnesaemia, bradycardia, congenital long QT syndrome, and any underlying cardiac pathology. Lastly, the risk associated with any given antipsychotic agent is increased if it is combined either with any other drug known to prolong the QT interval and provoke torsades de pointes, or with any drug capable of inhibiting the hepatic metabolism of the antipsychotic agent. A list of such drugs is provided, together with advice on the action to be taken when prescribing an antipsychotic agent to a patient with a long QT interval.


Cyclosporine and oxidized lipoproteins affect vascular reactivity. Influence of the endothelium.
Cyclosporine and in particular oxidatively modified low density lipoproteins can both exert direct vasoconstricting effects. We hypothesized that coincubation of arteries with low density lipoproteins and cyclosporine would enhance their respective influence on vascular tone. Therefore, we investigated vascular reactivity of isolated intact rabbit renal arteries preincubated with cyclosporine in the presence of native and oxidized low density lipoproteins. After preincubation of the arteries with cyclosporine (10 micrograms/ml, 90 minutes), unstimulated vascular tone as well as norepinephrine-induced vasoconstrictions remained unchanged compared with controls preincubated with the cyclosporine solvent dimethyl sulfoxide. Oxidized low density lipoproteins (100 micrograms/ml) in the absence of cyclosporine significantly enhanced vasoconstrictions to threshold concentrations of norepinephrine (78 +/- 10 microns at 30 nM). However, after cyclosporine treatment, the oxidized low density lipoprotein-induced potentiation of contractile responses to norepinephrine was further enhanced (157 +/- 19 versus 71 +/- 11 microns). Native low density lipoproteins had no influence on vascular tone. Potentiation of norepinephrine-induced vasoconstriction by oxidized low density lipoproteins took place in either endothelium-denuded or endothelium-intact arteries, whereas the further enhancement of vascular tone after cyclosporine treatment was seen only in endothelium-intact segments. Endothelium-dependent dilations to acetylcholine were fully preserved after treatment with oxidized low density lipoproteins and cyclosporine. Indomethacin, saralasin, and the thromboxane A2 antagonist daltroban had no influence, but the Ca2+ antagonist verapamil prevented the potentiation of vasoconstrictions by cyclosporine and oxidized low density lipoproteins.(ABSTRACT TRUNCATED AT 250 WORDS)


Electrocardiographic findings in patients with primary dysmenorrhea.
Primary dysmenorrhea (PD), which is characterized by painful menstrual cycles, is one of the common clinical problems in young adult women. The aim of this study was to investigate the risk of cardiac arrhythmias in PD patients by using the electrocardiographic (ECG) parameters. Forty patients diagnosed with PD and 30 age-matched normal controls were included in this study. ECGs were performed by using 12-leads with 10 mV amplitude and 25 mm/sec velocity. P and QT waves were manually marked along the isoelectric line. P maximum, P minimum, QT maximum and QT minimum were measured on the surface 12-leads ECG, and the P wave and QT dispersions were calculated. There was not any significant correlation of P wave dispersion and QT dispersion between the age, sex, body mass index, hemoglobin, fasting blood glucose or any other laboratory parameters. P wave dispersion was significantly longer in the PD group than the control group (61.4 ± 19 msec versus 57 ± 14 msec, P = 0.01). The P minimum duration was significantly shorter in the PD group compared with the control group (36 ± 16 msec versus 41 ± 9 msec, P = 0.03). QT dispersion was significantly higher in the PD group compared with normal controls (76 ± 23 msec versus 58 ± 16 msec, P = 0.02). These results show that PD can be associated with cardiac arrhythmias, especially atrial fibrillation, by increasing P wave dispersion and ventricular arrhythmia risk because of an increased QT interval.


Genomic Landscape of Experimental Bladder Cancer in Rodents and Its Application to Human Bladder Cancer: Gene Amplification and Potential Overexpression of Cyp2a5/CYP2A6 Are Associated with the Invasive Phenotype.
Non-muscle invasive (superficial) bladder cancer is a low-grade malignancy with good prognosis, while muscle invasive (invasive) bladder cancer is a high-grade malignancy with poor prognosis. N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) induces superficial bladder cancers with papillary morphology in rats and invasive bladder cancers with infiltrating phenotype in mice. In this study, we analyzed genomic landscapes of rodent BBN-induced bladder cancers using array-based comparative genomic hybridization (array CGH). While no significant copy number alterations were detected in superficial bladder tumors in rats, copy number gains in chromosomal regions 2D-E1, 7qA3, 9F2, and 11C-D were detected in invasive bladder tumors in mice. Amplification of representative genes located on 2D-E1 and 7qA3 chromosomal regions was confirmed by quantitative PCR. Cyp2a22 and Cyp2a5 genes but not Cyp2g1, Cyp2a12, and Rab4b genes on mouse chromosome 7qA3 were amplified in invasive bladder cancers. Although the human ortholog gene of Cyp2a22 has not been confirmed, the mouse Cyp2a5 gene is the ortholog of the human CYP2A6 gene located in chromosomal region 19q13.2, and CYP2A6 was identified by database search as one of the closest human homolog to mouse Cyp2a22. Considering a possibility that this region may be related to mouse 7qA3, we analyzed CYP2A6 copy number and expression in human bladder cancer using cell lines and resected tumor specimens. Although only one of eight cell lines showed more than one copy increase of the CYP2A6 gene, CYP2A6 amplification was detected in six out of 18 primary bladder tumors where it was associated with the invasive phenotype. Immunohistochemical analyses of 118 primary bladder tumors revealed that CYP2A6 protein expression was also higher in invasive tumors, especially in those of the scattered type. Together, these findings indicate that the amplification and overexpression of the CYP2A6 gene are characteristic of human bladder cancers with increased malignancy and that CYP2A6 can be a candidate prognostic biomarker in this type of cancer.


Pharmacology of rosemary (Rosmarinus officinalis Linn.) and its therapeutic potentials.
The use of plants is as old as the mankind. Natural products are cheap and claimed to be safe. They are also suitable raw material for production of new synthetic agents. Rosemary (Rosmarinus officinalis Linn.) is a common household plant grown in many parts of the world. It is used for flavouring food, a beverage drink, as well as in cosmetics; in folk.medicine it is used as an antispasmodic in renal colic and dysmenorrhoea, in relieving respiratory disorders and to stimulate growth of hair. Extract of rosemary relaxes smooth muscles of trachea and intestine, and has choleretic, hepatoprotective and antitumerogenic activity. The most important constituents of rosemary are caffeic acid and its derivatives such as rosmarinic acid. These compounds have antioxidant effect. The phenolic compound, rosmarinic acid, obtains one of its phenolic rings from phenylalanine via caffeic acid and the other from tyrosine via dihydroxyphenyl-lactic acid. Relatively large-scale production of rosmarinic acid can be obtained from the cell culture of Coleus blumei Benth when supplied exogenously with phenylalanine and tyrosine. Rosmarinic acid is well absorbed from gastrointestinal tract and from the skin. It increases the production of prostaglandin E2 and reduces the production of leukotriene B4 in human polymorphonuclear leucocytes, and inhibits the complement system. It is concluded that rosemary and its constituents especially caffeic acid derivatives such as rosmarinic acid have a therapeutic potential in treatment or prevention of bronchial asthma, spasmogenic disorders, peptic ulcer, inflammatory diseases, hepatotoxicity, atherosclerosis, ischaemic heart disease, cataract, cancer and poor sperm motility.


Bridging the gap between systems biology and medicine.
Systems biology has matured considerably as a discipline over the last decade, yet some of the key challenges separating current research efforts in systems biology and clinically useful results are only now becoming apparent. As these gaps are better defined, the new discipline of systems medicine is emerging as a translational extension of systems biology. How is systems medicine defined? What are relevant ontologies for systems medicine? What are the key theoretic and methodologic challenges facing computational disease modeling? How are inaccurate and incomplete data, and uncertain biologic knowledge best synthesized in useful computational models? Does network analysis provide clinically useful insight? We discuss the outstanding difficulties in translating a rapidly growing body of data into knowledge usable at the bedside. Although core-specific challenges are best met by specialized groups, it appears fundamental that such efforts should be guided by a roadmap for systems medicine drafted by a coalition of scientists from the clinical, experimental, computational, and theoretic domains.


Effect of egg washing on the cuticle quality of brown and white table eggs.
Egg washing is currently not permitted within the European Union, with few exceptions. This is mainly because there are concerns that cuticle damage could occur during or after the washing process, as a result of a suboptimal operation. In this study, the cuticle coverage levels of 400 washed or unwashed eggs, derived from either a brown or a white egg-laying flock at the end of lay, were compared. The eggs from older hens inherently have poorer cuticle coverage and as a result arguably constitute a greater risk to consumer safety if they are then washed. Thus, the effects of the washing procedure used in this study on cuticle quality were tested under the worst-case scenario. A standard Swedish egg washing process was used. The cuticle coverage of the eggs was assessed by a colorimeter by quantifying the color difference before and after staining with Tartrazine and Green S. The cuticle of an additional 30 eggs from each of the four groups was then visually assessed by scanning electron microscopy. The staining characteristics of the cuticle varied greatly within each group of eggs and showed that the washing process did not lead to cuticle damage. Scanning electron microscopy confirmed that there was no irreversible damage to the cuticle of the washed eggs and that it was not possible to correctly assign the treatment (washed or not) based on a visual assessment. In conclusion, no evidence could be found to suggest that the washing procedure used in this investigation irreversibly changed the quality of the cuticle.


Methods for the study of calcium oxalate crystallisation and their application to urolithiasis research.
Many methods have been used to study calcium oxalate crystallisation. Most can be characterised by changes in supersaturation during the experiment, which may increase, remain constant or decay. Their ability to quantify various aspects of crystallisation often reflects the extent to which nucleation, growth and aggregation can be measured independently, when two or three of these processes may be occurring simultaneously. The mixed suspension, mixed product removal technique reaches a steady state supersaturation, is a good model for intrarenal crystallisation and allows both growth and nucleation rates to be measured. Using 92% urine and comparing control urines with samples from recurrent stone formers no difference in growth rates was found but the controls had higher nucleation rates (p = 0.003) and lower supersaturations (p = 0.001). In parallel crystallisers running simultaneously, heparin or hyaluronic acid addition to 92% urine was studied. Both macromolecules increased growth rates, decreased nucleation rates and increased supersaturation (p < 0.05). The steady state supersaturation achieved in this system may be an important determinant of stone forming potential. The ability to reach a lower urinary supersaturation by increased nucleation may be a crucial protective factor distinguishing non stone formers from stone formers.


The design of trapping devices in pollination traps of the genus Arum (Araceae) is related to insect type.
Pollinators have long been known to select for floral traits, but the nature of this relationship has been little investigated in trap pollination systems. We investigated the trapping devices of 15 Arum spp. and compared them with the types of insects trapped. Most species shared a similar general design of trap chamber walls covered in downward-pointing papillate cells, lacunose cells in the chamber wall and elongated sterile flowers partially blocking the exit of the trap. However, there was significant variation in all these morphological features between species. Furthermore, these differences related to the type of pollinator trapped. Most strikingly, species pollinated by midges had a slippery epidermal surface consisting of smaller papillae than in species pollinated by other insects. Midge-pollinated species also had more elongated sterile flowers and tended to have a larger lacunose area. We conclude that pollination traps evolve in response to the type of insect trapped and that changes to the slippery surfaces of the chamber wall are an important and previously little recognized variable in the design of pollination traps.


Predialysis NTproBNP predicts magnitude of extracellular volume overload in haemodialysis patients.
Increased natriuretic peptides are associated with increased cardiovascular and all-cause mortality for haemodialysis (HD) patients. However, debate continues whether these biomarkers are increased by extracellular water (ECW) excess and can be used to aid clinical assessment of volume status and help determine target weight. We measured N terminal probrain natriuretic peptide (NT-proBNP) predialysis in 375 stable haemodialysis outpatients with corresponding pre and postdialysis multifrequency bioelectrical impedance assessments (MFBIA) of (ECW)/total body water (TBW). Median age 64 (51-75), 63.9% male, 42.9% diabetic, 43.2% Caucasoid, 14.4% with a history of myocardial infarction, 8.4% coronary artery bypass surgery, dialysis vintage 28.2 (12.3-55.5) months. Median predialysis NT-proBNP 283 (123-989) pmol/l, and predialysis ECW/TBW ratio 0.397 ± 0.029. On multivariate analysis, predialysis log NT-proBNP was associated with predialysis systolic blood pressure (β 0.007, p = 0.000), weight (β -0.008, p = 0.001), valvular heart disease (β 0.342, p = 0.015, ECW/TBW (β 1.3, p = 0.019) and log CRP (β 0.145, p = 0.037). Dividing patients into NTproBNP quartiles, %ECW/TBW and relative ECW overhydration were significantly greater for the highest quartile vs. lowest (40.5 ± 4.1 vs. 39.0 ± 1.1, and 1.51 ± 1.24 vs. 0.61 ± 0.69 l, respectively, p < 0.001). In this study, predialysis NTproBNP values were associated with direct assessments of the extracellular volume excess measured by MFBIA and systolic arterial blood pressure. This suggests that predialysis NTproBNP values can potentially be used to aid clinical assessment of volume status in dialysis patients to determine target weight.


Mediterranean Diet Adherence among Preschoolers and its Association with Parents' Beliefs, Attitudes, and Practices.
The effect of parents on nutritional habits in preschool children is undeniable. It is known that parental control in child nutrition can affect the child's eating habits, and bodyweight. Mediterranean Diet (MD) adherence of children (KIDMED), parents' beliefs, attitudes and practices (Preschool Feeding Questionnaire-PFQ2) were investigated. The questionnaire prepared was applied by researchers face-to-face to 1413 families who agreed to participate voluntarily in the research with preschool children. Parental beliefs, attitudes, and practices regarding child nutrition status of parents were evaluated using 39-item PFQ2 and their child's eating habits using the 16-item KIDMED index. Children's KIDMED scores were found optimal in 34.1%, average in 57.0%, very low in 8.9%. The KIDMED scores of children whose parents are together (6.6 ± 2.1) were found to be significantly higher than children whose parents are separated (4.9 ± 2.2) (p <.001). A correlation was found between the KIDMED scores of the children, the parental control (r = 0.156, p <.001), maternal restriction (r = 0.104, p <.001), and structured feeding (r = 0.162, p <.001). Unfortunately, the adherence of most preschool children with the MD which considered a healthy diet pattern was found below the optimal level.


A meta-analysis of crop response patterns to nitrogen limitation for improved model representation.
The representation of carbon-nitrogen (N) interactions in global models of the natural or managed land surface remains an important knowledge gap. To improve global process-based models we require a better understanding of how N limitation affects photosynthesis and plant growth. Here we present the findings of a meta-analysis to quantitatively assess the impact of N limitation on source (photosynthate production) versus sink (photosynthate use) activity, based on 77 highly controlled experimental N availability studies on 11 crop species. Using meta-regressions, we find that it can be insufficient to represent N limitation in models merely as inhibiting carbon assimilation, because in crops complete N limitation more strongly influences leaf area expansion (-50%) than photosynthesis (-34%), while leaf starch is accumulating (+83%). Our analysis thus offers support for the hypothesis of sink limitation of photosynthesis and encourages the exploration of more sink-driven crop modelling approaches. We also show that leaf N concentration changes with N availability and that the allocation of N to Rubisco is reduced more strongly compared to other photosynthetic proteins at low N availability. Furthermore, our results suggest that different crop species show generally similar response patterns to N limitation, with the exception of leguminous crops, which respond differently. Our meta-analysis offers lessons for the improved depiction of N limitation in global terrestrial ecosystem models, as well as highlights knowledge gaps that need to be filled by future experimental studies on crop N limitation response.


Preoperative Renal Insufficiency: Underreporting and Association With Readmission and Major Postoperative Morbidity in an Academic Medical Center.
Making a formal diagnosis of chronic kidney disease (CKD) in the preoperative setting may be challenging because of lack of longitudinal data. We explored the predictive value of a single reduced preoperative estimated glomerular filtration rate (eGFR) value on adverse patient outcomes in the first 30 days after elective surgery. We compared the rate of major postoperative adverse events, including 30-day readmission rate, hospital length of stay, infection, acute kidney injury (AKI), and myocardial infarction across patients with declining preoperative eGFR values. We hypothesized that there is an association between decreasing preoperative eGFR values and major postoperative morbidity including readmission within 30 days of discharge and that the reasons for unplanned readmissions may be associated with poor preoperative renal function. This was a retrospective analysis of the electronic health record of 39 989 adult patients who underwent elective surgery between June 2011 and July 2013 at our institution. Patients with reduced eGFR (<60 mL/min/1.73 m) were identified and categorized by the stages of CKD that correlated with the preoperative eGFR value. Odds of readmission to our hospital within 30 days, as well as new diagnosis of AKI, myocardial infarction, and infection, were determined with multivariate logistic regression. The subset of patients who were readmitted within 30 days also were subdivided further into patients who had an eGFR <60 mL/min/1.73 m and those with an eGFR ≥60 mL/min/1.73 m, as well as whether the readmission was planned or unplanned. Of the 4053 patients with eGFR <60 mL/min/1.73 m, 3290 (81.2%) did not carry a preoperative diagnosis of CKD. Adjusted odds ratios of being readmitted were 1.48 (99% confidence interval [CI], 1.18-1.87; P < .001) for eGFR 30 to 44 mL/min/1.73 m to 2.06 (99% CI, 1.32-3.23; P < .001) for eGFR <15 mL/min/1.73 m compared with patients with a preoperative eGFR value ≥60 mL/min/1.73 m. Patients with a lower eGFR also demonstrated increasing odds of AKI from 2.78 (99% CI, 1.86-4.17; P < .001) for eGFR 45 to 59 mL/min/1.73 m to 3.81 (99% CI, 1.68-8.16; P < .001) for eGFR <15 mL/min/1.73 m. This study highlights that preoperative renal insufficiency may be underreported and appears to be significantly associated with postoperative complications. It extends the association between a single low preoperative eGFR and postoperative morbidity to a broader range of surgical populations than previously described. Our results suggest that preoperative calculation of eGFR may be a relatively low-cost, readily available tool to identify patients who are at an increased risk of readmission within 30 days of surgery and postoperative morbidity in patients presenting for elective surgery.


Quantification of nascent transcription by bromouridine immunocapture nuclear run-on RT-qPCR.
Nuclear run-on (NRO) is a method that measures transcriptional activity via the quantification of biochemically labeled nascent RNA molecules derived from nuclear isolates. Widespread use of this technique has been limited because of its technical difficulty relative to steady-state total mRNA analyses. Here we describe a detailed protocol for the quantification of transcriptional activity in human cell cultures. Nuclei are first isolated and NRO transcription is performed in the presence of bromouridine. Labeled nascent transcripts are purified by immunoprecipitation, and transcript levels are determined by reverse-transcription quantitative PCR (RT-qPCR). Data are then analyzed using standard techniques described elsewhere. This method is rapid (the protocol can be completed in 2 d) and cost-effective, exhibits negligible detection of background noise from unlabeled transcripts, requires no radioactive materials and can be performed from as few as 500,000 nuclei. It also takes advantage of the high sensitivity, specificity and dynamic range of RT-qPCR.


The economic costs and benefits of dental education: an empirical analysis.
The rising costs associated with obtaining a dental education have caused some to question the financial benefit of pursuing a dental degree. There is a concern that recent graduates may have difficulty finding professional opportunities that provide the income necessary to service their accumulated educational debt. The aim of this study was to evaluate the trends in educational costs to aid in making an accurate appraisal of the financial benefit of a dental education. Adjusted into constant dollar terms, data from a variety of sources were collected for economic variables such as tuition, fees, student indebtedness, and dentists' earnings. These variables were then analyzed to determine the true costs and benefits of obtaining a dental education. The results showed that, over the course of the last decade, educational costs increased faster than the real net income of practicing dentists, which led to a decline in the return on investment in dental education. However, regardless of an applicant's choice of public or private dental school, there continues to be a positive economic return on students' commitment of both financial resources and time to receive a dental education.


Broadband light management using low-Q whispering gallery modes in spherical nanoshells.
Light trapping across a wide band of frequencies is important for applications such as solar cells and photodetectors. Here, we demonstrate a new approach to light management by forming whispering-gallery resonant modes inside a spherical nanoshell structure. The geometry of the structure gives rise to a low quality-factor, facilitating the coupling of light into the resonant modes and substantial enhancement of the light path in the active material, thus dramatically improving absorption. Using nanocrystalline silicon (nc-Si) as a model system, we observe broadband absorption enhancement across a large range of incident angles. The absorption of a single layer of 50-nm-thick spherical nanoshells is equivalent to a 1-μm-thick planar nc-Si film. This light-trapping structure could enable the manufacturing of high-throughput ultra-thin film absorbers in a variety of material systems that demand shorter deposition time, less material usage and transferability to flexible substrates.


Molecular structure of charybdotoxin, a pore-directed inhibitor of potassium ion channels.
The three-dimensional structure of charybdotoxin, a high-affinity peptide blocker of several potassium ion channels, was determined by two-dimensional nuclear magnetic resonance (2-D NMR) spectroscopy. Unambiguous NMR assignments of backbone and side chain hydrogens were made for all 37 amino acids. The structure was determined by distance geometry and refined by nuclear Overhauser and exchange spectroscopy back calculation. The peptide is built on a foundation of three antiparallel beta strands to which other parts of the sequence are attached by three disulfide bridges. The overall shape is roughly ellipsoidal, with axes of approximately 2.5 and 1.5 nanometers. Nine of the ten charged groups are located on one side of the ellipsoid, with seven of the eight positive residues lying in a stripe 2.5 nanometers in length. The other side displays three hydrophobic residues projecting prominently into aqueous solution. The structure rationalizes several mechanistic features of charybdotoxin block of the high-conductance Ca2(+)-activated K+ channel.


Outpatient morbidity in Slavonski Brod during 1991/1992 war in Croatia.
Indirect effects of war on the health status of population in Slavonski Brod, Croatia, were assessed. The study was based on registered outpatient morbidity data in General Practice Service of Slavonski Brod Medical Centre. Data from a pre-war period (January-June 1991) were compared to the war data (July-December 1991). Health care utilization and morbidity rates significantly differed in the two time periods. The most prominent were decreased consultations rates (40%) and increased rates of intestinal infections (80%), skin infections (20%) and injuries (50%). Numerous other changes were found, but all could not be related to the war. Although the indirect war effects on health were minimal at the time of investigation, the process was visible and must be continuously observed.


Tests for the replication of an association between Egfr and natural variation in Drosophila melanogaster wing morphology.
Quantitative differences between individuals stem from a combination of genetic and environmental factors, with the heritable variation being shaped by evolutionary forces. Drosophila wing shape has emerged as an attractive system for genetic dissection of multi-dimensional traits. We utilize several experimental genetic methods to validation of the contribution of several polymorphisms in the Epidermal growth factor receptor (Egfr) gene to wing shape and size, that were previously mapped in populations of Drosophila melanogaster from North Carolina (NC) and California (CA). This re-evaluation utilized different genetic testcrosses to generate heterozygous individuals with a variety of genetic backgrounds as well as sampling of new alleles from Kenyan stocks. Only one variant, in the Egfr promoter, had replicable effects in all new experiments. However, expanded genotyping of the initial sample of inbred lines rendered the association non-significant in the CA population, while it persisted in the NC sample, suggesting population specific modification of the quantitative trait nucleotide QTN effect. Dissection of quantitative trait variation to the nucleotide level can identify sites with replicable effects as small as one percent of the segregating genetic variation. However, the testcross approach to validate QTNs is both labor intensive and time-consuming, and is probably less useful than resampling of large independent sets of outbred individuals.


Redox Interconversion of Non-Oxido Vanadium Complexes Accompanied by Acid-Base Chemistry of Thiol and Thiolate.
The redox nature of the non-oxido vanadium sulfur center is associated with several biological systems such as vanadium nitrogenase, the reduction of vanadium ion in ascidians, and the function of amavadin, which is a vanadium(IV) natural product contained in Amanita mushrooms. But the related chemistry is less explored and understood compared to oxido vanadium species due to the oxophilic character of high valent vanadium ions. Herein, we present a class of non-oxido vanadium thiolate complexes, [VIII(PS2″SH)2]- (1) (PS2″SH = [P(C6H3-3-Me3Si-2-S)2(C6H3-3-Me3Si-2-SH)]2-), [VIV(PS3″)(PS2″SH)]- (2) (PS3″ = [P(C6H3-3-Me3Si-2-S)3]3-), [V(PS3″)2]- (3), [V(PS3″)(PS2″SH)] (4), and [VIV(PS3*)2]2- (5a) (PS3* = [P(C6H3-3-Ph-2-S)3]3-), and study their interconversion through the redox and acid-base reactions. Complex 1 consists of a six-coordinate octahedral vanadium center; complexes 2 and 4 are seven-coordinate with distorted capped trigonal prismatic geometry. Vanadium centers of 3 and 5a are both eight-coordinate; the former adopts ideal dodecahedral geometry, but the latter is better viewed as a distorted square antiprism. Complex 1 is oxidized to complex 2 and then to complex 3 with dioxygen. Each one-electron oxidation process is accompanied by the deprotonation of unbound thiol to bound thiolate. Complex 3 is also produced from complex 2 through stepwise addition of Fe(Cp)2+/n-BuLi, or in the reverse order. The formation of 2 from 3 is achieved in the order of adding Co(Cp)2 and acid or, as with the previous complex, inversely. Notably, the reduction of complex 2 to complex 1 accompanying the protonation of bound thiolate to unbound thiol only occurs with the presence of both Co(Cp)2 and acid, indicating a cooperative effect between the metal-centered reduction and bound thiolate protonation. The conversions among these complexes are observed with ESI-MS and UV-vis-NIR spectroscopies. The work demonstrates two-electron redox interconversion in these complexes mediated by transformations between unbound thiol and bound thiolate.


Determination of hepatoprotective and antioxidant role of walnuts against ethanol-induced oxidative stress in rats.
The aims of our study were the evaluation of the hepatoprotective effect and antioxidant role of walnuts against ethanol-induced oxidative stress. The hepatoprotective and antioxidant role of the walnuts supplementation feed against ethanol-induced oxidative stress were evaluated by measuring liver damage serum marker enzymes; aspartate aminotransferase (AST); alanine aminotransferase (ALT); gamma glutamyl transpeptidase (GGT); lactate dehydrogenase (LDH); and antioxidant defense systems such as reduced glutathione, glutathione reductase, superoxide dismutase, glutathione-S-transferase, catalase, and glutathione peroxidase and Malondialdehyde (MDA) content in various tissues of rats. Rats were divided into six experimental groups: I (control), II (20 % ethanol), III (10 % walnuts), IV (20 % ethanol + 10 % walnuts), V (5 % walnuts), and VI (20 % ethanol + 5 % walnuts). According to the results, the biochemical analysis showed a considerable increase in the serum aspartate AST, ALT, GGT, and LDH in the group II as compared to that of group I, whereas decreased in group IVas compared to that of group II. In addition, administration of walnuts supplementation restored the ethanol-induced imbalance between MDA and fluctuated antioxidant system toward close control group particularly in the tissues. The results indicated that walnuts could be as important as diet-derived antioxidants in preventing oxidative damage in the tissues by reducing the lipid oxidation or inhibiting the production of ethanol-induced free radicals in rats.


Anthropometry at birth and at age of routine vaccination to predict mortality in the first year of life: A birth cohort study in BukinaFaso.
The World Health Organization currently defines severe acute malnutrition (SAM) in infants aged under 6 months of age using weight-for-length Z score (WLZ). Given widespread use of mid-upper arm circumference (MUAC) for identifying SAM in older children and weight-for-age (WAZ) for growth monitoring, there is increasing debate about the optimal anthropometric criteria to best identify infants u6m at-risk of mortality. To determine the discriminatory value for mortality during the first 12 months of life of anthropometry taken at birth and at age two months (approximate age of routine vaccination). Data were analyzed from a birth cohort recruited between April and December of 2004 at four health facilities within Bansalogho District in Burkina Faso. Infants were followed up for 12 months. Mortality risks were estimated using hazards ratios (HR). Discriminatory value was assessed using receiver operating characteristic curves. Of 1,103 infants, 227 (21%) were low birthweight (LBW). During 12 months, 86 (7.8%) infants died; 38 (44%) among the LBW group. At birth, MUAC<9.0cm, weight<2.5kg, length<44.2cm and incalculable WLZ were associated with mortality. Sixty (70%) deaths occurred after the age of two months; 26 (43%) among LBW infants. At age two months, any MUAC <11.5cm, weight <3.8kg (WAZ<-3) and length <52.4cm (LAZ<-3) were associated with risk of mortality. WLZ was not associated with mortality at any threshold. Birth weight did not modify the effect of the association between month two MUAC and one-year mortality (P = 0.33). Infants at heightened risk of mortality and are better identified during early infancy by MUAC or WFA than by WLZ. LBW infants with low anthropometry at the age of routine immunizations remain at elevated risk than normal birth weight (NBW)infants and require intervention. Effectiveness, cost-effectiveness and coverage of applying proposed thresholds should be investigated as a priority to inform policy and practice.


Avidin Adsorption to Silk Fibroin Films as a Facile Method for Functionalization.
Silk fibroin biomaterials are highly versatile in terms of materials formation and functionalization, with applications in tissue engineering and drug delivery, but necessitate modifications for optimized biological activity. Herein, a facile, avidin-based technique is developed to noncovalently functionalize silk materials with bioactive molecules. The ability to adsorb avidin to silk surfaces and subsequently couple biotinylated macromolecules via avidin-biotin interaction is described. This method better preserved functionality than standard covalent coupling techniques using carbodiimide cross-linking chemistry. The controlled release of avidin from the silk surface was demonstrated by altering the adsorption parameters. Application of this technique to culturing human foreskin fibroblasts (hFFs) and human mesenchymal stem cells (hMSCs) on arginine-glycine-aspartic-acid-modified (RGD-modified) silk showed increased cell growth over a seven-day period. This technique provides a facile method for the versatile functionalization of silk materials for biomedical applications including tissue engineering, drug delivery, and biological sensing.


Exercise therapy for fatigue in multiple sclerosis.
Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system affecting an estimated 1.3 million people worldwide. It is characterised by a variety of disabling symptoms of which excessive fatigue is the most frequent. Fatigue is often reported as the most invalidating symptom in people with MS. Various mechanisms directly and indirectly related to the disease and physical inactivity have been proposed to contribute to the degree of fatigue. Exercise therapy can induce physiological and psychological changes that may counter these mechanisms and reduce fatigue in MS. To determine the effectiveness and safety of exercise therapy compared to a no-exercise control condition or another intervention on fatigue, measured with self-reported questionnaires, of people with MS. We searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Trials Specialised Register, which, among other sources, contains trials from: the Cochrane Central Register of Controlled Trials (CENTRAL) (2014, Issue 10), MEDLINE (from 1966 to October 2014), EMBASE (from 1974 to October 2014), CINAHL (from 1981 to October 2014), LILACS (from 1982 to October 2014), PEDro (from 1999 to October 2014), and Clinical trials registries (October 2014). Two review authors independently screened the reference lists of identified trials and related reviews. We included randomized controlled trials (RCTs) evaluating the efficacy of exercise therapy compared to no exercise therapy or other interventions for adults with MS that included subjective fatigue as an outcome. In these trials, fatigue should have been measured using questionnaires that primarily assessed fatigue or sub-scales of questionnaires that measured fatigue or sub-scales of questionnaires not primarily designed for the assessment of fatigue but explicitly used as such. Two review authors independently selected the articles, extracted data, and determined methodological quality of the included trials. Methodological quality was determined by means of the Cochrane 'risk of bias' tool and the PEDro scale. The combined body of evidence was summarised using the GRADE approach. The results were aggregated using meta-analysis for those trials that provided sufficient data to do so. Forty-five trials, studying 69 exercise interventions, were eligible for this review, including 2250 people with MS. The prescribed exercise interventions were categorised as endurance training (23 interventions), muscle power training (nine interventions), task-oriented training (five interventions), mixed training (15 interventions), or 'other' (e.g. yoga; 17 interventions). Thirty-six included trials (1603 participants) provided sufficient data on the outcome of fatigue for meta-analysis. In general, exercise interventions were studied in mostly participants with the relapsing-remitting MS phenotype, and with an Expanded Disability Status Scale less than 6.0. Based on 26 trials that used a non-exercise control, we found a significant effect on fatigue in favour of exercise therapy (standardized mean difference (SMD) -0.53, 95% confidence interval (CI) -0.73 to -0.33; P value < 0.01). However, there was significant heterogeneity between trials (I(2) > 58%). The mean methodological quality, as well as the combined body of evidence, was moderate. When considering the different types of exercise therapy, we found a significant effect on fatigue in favour of exercise therapy compared to no exercise for endurance training (SMDfixed effect -0.43, 95% CI -0.69 to -0.17; P value < 0.01), mixed training (SMDrandom effect -0.73, 95% CI -1.23 to -0.23; P value < 0.01), and 'other' training (SMDfixed effect -0.54, 95% CI -0.79 to -0.29; P value < 0.01). Across all studies, one fall was reported. Given the number of MS relapses reported for the exercise condition (N = 25) and non-exercise control condition (N = 26), exercise does not seem to be associated with a significant risk of a MS relapse. However, in general, MS relapses were defined and reported poorly. Exercise therapy can be prescribed in people with MS without harm. Exercise therapy, and particularly endurance, mixed, or 'other' training, may reduce self reported fatigue. However, there are still some important methodological issues to overcome. Unfortunately, most trials did not explicitly include people who experienced fatigue, did not target the therapy on fatigue specifically, and did not use a validated measure of fatigue as the primary measurement of outcome.


Evaluation of fluorescence-based amplified fragment length polymorphism analysis for molecular typing in hospital epidemiology: comparison with pulsed-field gel electrophoresis for typing strains of vancomycin-resistant Enterococcus faecium.
Fluorescence-based amplified fragment length polymorphism (fbAFLP) is a novel assay based on the fluorescent analysis of an amplified subset of restriction fragments. The fbAFLP assay involves the selective PCR amplification of restriction fragments from a total digest of genomic DNA. The ligation of adapters with primer-specific sites coupled with primers containing selective nucleotides allowed the full potential of PCR to be realized while maintaining the advantages of restriction endonuclease analysis. Fluorescence-based fragment analysis with polyacrylamide gel electrophoresis provides the accurate band sizing required for homology assessment. The large number of phylogenetically informative characters obtained by fbAFLP is well suited for cluster analysis and database development. The method demonstrated excellent reproducibility and ease of performance and interpretation. We typed 30 epidemiologically well-characterized isolates of vancomycin-resistant enterococci from an outbreak in a university hospital by fbAFLP. Clustering of fbAFLP data matched epidemiological, microbiological, and pulsed-field gel electrophoresis data. This study demonstrates the unprecedented utility of fbAFLP for epidemiological investigation. Future developments in standardization and automation will set fbAFLP as the "gold standard" for molecular typing in epidemiology.


The golden beauty: brain response to classical and renaissance sculptures.
Is there an objective, biological basis for the experience of beauty in art? Or is aesthetic experience entirely subjective? Using fMRI technique, we addressed this question by presenting viewers, naïve to art criticism, with images of masterpieces of Classical and Renaissance sculpture. Employing proportion as the independent variable, we produced two sets of stimuli: one composed of images of original sculptures; the other of a modified version of the same images. The stimuli were presented in three conditions: observation, aesthetic judgment, and proportion judgment. In the observation condition, the viewers were required to observe the images with the same mind-set as if they were in a museum. In the other two conditions they were required to give an aesthetic or proportion judgment on the same images. Two types of analyses were carried out: one which contrasted brain response to the canonical and the modified sculptures, and one which contrasted beautiful vs. ugly sculptures as judged by each volunteer. The most striking result was that the observation of original sculptures, relative to the modified ones, produced activation of the right insula as well as of some lateral and medial cortical areas (lateral occipital gyrus, precuneus and prefrontal areas). The activation of the insula was particularly strong during the observation condition. Most interestingly, when volunteers were required to give an overt aesthetic judgment, the images judged as beautiful selectively activated the right amygdala, relative to those judged as ugly. We conclude that, in observers naïve to art criticism, the sense of beauty is mediated by two non-mutually exclusive processes: one based on a joint activation of sets of cortical neurons, triggered by parameters intrinsic to the stimuli, and the insula (objective beauty); the other based on the activation of the amygdala, driven by one's own emotional experiences (subjective beauty).


The role of sociodemographic factors in maternal psychological distress and mother-preterm infant interactions.
Preterm birth has been associated with greater psychological distress and less positive mother infant interactions than were experienced by mothers of full-term infants. Maternal and infant sociodemographic factors have also shown a strong association with psychological distress and the mother-infant relationship. However, findings on their effects over time are limited. In this longitudinal analysis, we explored the relationship of maternal and infant sociodemographic variables (maternal age, maternal education, marital status, being on social assistance, maternal race, infant birth weight, and infant gender) to maternal psychological distress (depressive, posttraumatic stress, anxiety, parenting stress symptoms, and maternal worry about child's health) through 12 months corrected age for prematurity, and on the home environment, and mother-infant interactions through 6 months corrected age for prematurity. We also explored differences related to maternal obstetrical characteristics (gestational age at birth, parity, mode of delivery, and multiple birth) and severity of infant conditions (Apgar scores, need for mechanical ventilation, and infant medical complications). Although the relationship of maternal and infant characteristics with these outcomes did not change over time, psychological distress differed based on marital status, maternal education, infant gender, and infant medical complications. Older mothers provided more a positive home environment. Mother-infant interactions differed by maternal age, being on public assistance, maternal race, infant gender, and infant medical complications. More longitudinal research is needed to better understand these effects over time in order to identify and support at-risk mothers.


Structure elucidation of bacterial nonribosomal lipopeptides.
Nonribosomal lipopeptides (NRLPs) are complex natural products of bacterial origin that not only fulfill important ecological functions but also serve as lead structures for the development of new pharmaceuticals. In order to carry out detailed structure-activity relationship studies and to decipher the biological activities of NRLPs, the primary structure, including stereochemical assignment, of every new member of this natural product family has to be established first. In this review, we want to focus on analytical techniques and tools that can be employed to elucidate the structure of bacterial NRLPs.


The NF-κB p65 and p50 homodimer cooperate with IRF8 to activate iNOS transcription.
Inducible nitric oxide synthase (iNOS) metabolizes L-arginine to produce nitric oxide (NO) which was originally identified in myeloid cells as a host defense mechanism against pathogens. Recent studies, however, have revealed that iNOS is often induced in tumor cells and myeloid cells in the tumor microenvironment. Compelling experimental data have shown that iNOS promotes tumor development in certain cellular context and suppresses tumor development in other cellular conditions. The molecular mechanisms underlying these contrasting functions of iNOS is unknown. Because iNOS is often induced by inflammatory signals, it is therefore likely that these contrasting functions of iNOS could be controlled by the inflammatory signaling pathways, which remains to be determined. iNOS is expressed in colon carcinoma and myeloid cells in the tumor microenvironment. Colon carcinoma and myeloid cell lines were used to elucidate the molecular mechanisms underlying iNOS expression. Chromatin immunoprecipitation and electrophoretic mobility shift assay were used to determine the IFNγ-activated pSTAT1 and NF-κB association with the chromatin DNA of the nos2 promoter. We show here that iNOS is dramatically up-regulated in inflammed human colon tissues and in human colon carcinoma as compared to normal colon tissue. iNOS is expressed in either the colon carcinoma cells or immune cells within the tumor microenvironment. On the molecular level, the proinflammatory IFNγ and NF-κB signals induce iNOS expression in human colon cancer cells. We further demonstrate that NF-κB directly binds to the NOS2 promoter to regulate iNOS expression. Although neither the IFNγ signaling pathway nor the NF-κB signaling pathway alone is sufficient to induce iNOS expression in myeloid cells, IFNγ and NF-κB synergistically induce iNOS expression in myeloid cells. Furthermore, we determine that IFNγ up-regulates IRF8 expression to augment NF-κB induction of iNOS expression. More interestingly, we observed that the p65/p65 and p50/p50 homodimers, not the canonical p65/p50 heterodimer, directly binds to the nos2 promoter to regulate iNOS expression in myeloid cells. IFNγ-induced IRF8 acts in concert with NF-κB to regulate iNOS expression in both colon carcinoma and myeloid cells. In myeloid cells, the NF-κB complexes that bind to the nos2 promoter are p65/p65 and p50/p50 homodimers.


Vertical gastric plication versus Nissen fundoplication in the treatment of gastroesophageal reflux in children with cerebral palsy.
Association between neurological lesions and gastroesophageal reflux disease (GERD) in children is very common. When surgical treatment is indicated, the consensus favors the fundoplication technique recommended by Nissen, despite its high morbidity and relapse rates. Vertical gastric plication is a procedure that may have advantages over Nissen fundoplication, since it is less aggressive and more adequately meets anatomical principles. The authors proposed to compare the results from the Nissen and vertical gastric plication techniques. Randomized prospective study within the Postgraduate Surgery and Experimentation Program of UNIFESP-EPM, at Hospital do Servidor Público Estadual (IAMSPE) and Hospital Municipal Infantil Menino Jesus. Fourteen consecutive children with cerebral palsy attended between November 2003 and July 2004 were randomized into two groups for surgical treatment of GERD: NF, Nissen fundoplication (n = 7); and VGP, vertical gastric plication (n = 7). These were clinically assessed by scoring for signs and symptoms, evaluation of esophageal pH measurements, duration of the operation, intra and postoperative complications, mortality and length of hospital stay. The mean follow-up was 5.2 months; symptoms were reduced by 42.8% (NF) (p = 0.001) and 57.1% (VGP) (p = 0.006). The Boix-Ochoa score was favorable for both groups: NF (p < 0.001) and VGP (p < 0.042). The overall mortality was 14.28% in both groups and was due to causes unrelated to the surgical treatment. The two operative procedures were shown to be efficient and efficacious for the treatment of GERD in neuropathic patients, over the study period.


Superconducting Nanowire Spiking Element for Neural Networks.
As the limits of traditional von Neumann computing come into view, the brain's ability to communicate vast quantities of information using low-power spikes has become an increasing source of inspiration for alternative architectures. Key to the success of these largescale neural networks is a power-efficient spiking element that is scalable and easily interfaced with traditional control electronics. In this work, we present a spiking element fabricated from superconducting nanowires that has pulse energies on the order of ∼10 aJ. We demonstrate that the device reproduces essential characteristics of biological neurons, such as a refractory period and a firing threshold. Through simulations using experimentally measured device parameters, we show how nanowire-based networks may be used for inference in image recognition and that the probabilistic nature of nanowire switching may be exploited for modeling biological processes and for applications that rely on stochasticity.


Use of intrathecal baclofen administered by programmable infusion pumps in resistent spasticity.
On the basis of previous experimental and clinical studies patients with severe spasticity due to spinal cord damage from multiple sclerosis in 8 cases and postraumatic paraplegia in 6 and resistent to all conservative treatments were selected for a trial with morphine and baclofen administered intrathecally through a catheter placed in the spinal subarachnoid space rostral to the affected segments and attached to a subcutaneous reservoir. Whereas morphine single injection did not show any benefit, baclofen bolus injection 30 to 60 micrograms, revealed a marked decrease of spasticity and associated symptoms in 8 cases. After checking the clinical effect during 3 weeks and changes in electroneurophysiological studies and bladder manometry the catheter was attached to a subcutaneous programmable pump able to be refilled percutaneously and administered baclofen continuously or more often following a multistep complex programme in total doses of 90 to 150 micrograms per day. After a mean follow-up of 5 months all cases showed an absence of spasms and pain, a notable improvement for bettering of sphincter functions and a marked muscle relaxation that improves motor capacity, leading to increased ambulation or mobility. Neither complications nor side-effects were observed.


Effect of MWCNT size, carboxylation, and purification on in vitro and in vivo toxicity, inflammation and lung pathology.
Several properties of multi-walled carbon nanotubes (MWCNT) have the potential to affect their bioactivity. This study examined the in vitro and in vivo outcomes of the influence of diameter, length, purification and carboxylation (in vitro testing only) of MWCNT. Three original 'as received' MWCNT that varied in size (diameter and length) were purified and functionalized by carboxylation. The resulting MWCNT were characterized and examined for cytotoxicity and inflammasome activation in vitro using THP-1 cells and primary alveolar macrophages from C57BL/6 mice. Oropharyngeal aspiration administration was used to deliver original MWCNT and in vivo bioactivity and lung retention was examined at 1 and 7 days. Studies with THP-1 macrophages demonstrated that increased length or diameter corresponded with increased bioactivity as measured by inflammasome activation. Purification had little effect on the original MWCNT, and functionalization completely eliminated bioactivity. Similar results were obtained using alveolar macrophages isolated from C57BL/6 mice. The in vivo studies demonstrated that all three original MWCNT caused similar neutrophil influx at one day, but increasing length or diameter resulted in the lavaged cells to release more inflammatory cytokines (IL-6, TNF-α, and IL-1β) ex vivo. Seven-day histology revealed that, consistent with the in vitro results, increasing width or length of MWCNT caused more severe pathology with the longest MWCNT causing the most severe inflammation. In addition, the same two larger MWCNT were retained more in the lung at 7 days. Taken together, the results indicated that in vitro and in vivo bioactivity of MWCNT increased with diameter and length. Purification had no significant modifying effect from the original MWCNT. Functionalization by carboxylation completely eliminated the bioactive potential of the MWCNT regardless of size in in vitro testing.


Anoxic androgen degradation by the denitrifying bacterium Sterolibacterium denitrificans via the 2,3-seco pathway.
The biodegradation of steroids is a crucial biochemical process mediated exclusively by bacteria. So far, information concerning the anoxic catabolic pathways of androgens is largely unknown, which has prevented many environmental investigations. In this work, we show that Sterolibacterium denitrificans DSMZ 13999 can anaerobically mineralize testosterone and some C19 androgens. By using a (13)C-metabolomics approach and monitoring the sequential appearance of the intermediates, we demonstrated that S. denitrificans uses the 2,3-seco pathway to degrade testosterone under anoxic conditions. Furthermore, based on the identification of a C17 intermediate, we propose that the A-ring cleavage may be followed by the removal of a C2 side chain at C-5 of 17-hydroxy-1-oxo-2,3-seco-androstan-3-oic acid (the A-ring cleavage product) via retro-aldol reaction. The androgenic activities of the bacterial culture and the identified intermediates were assessed using the lacZ-based yeast androgen assay. The androgenic activity in the testosterone-grown S. denitrificans culture decreased significantly over time, indicating its ability to eliminate androgens. The A-ring cleavage intermediate (≤ 500 μM) did not exhibit androgenic activity, whereas the sterane-containing intermediates did. So far, only two androgen-degrading anaerobes (Sterolibacterium denitrificans DSMZ 13999 [a betaproteobacterium] and Steroidobacter denitrificans DSMZ 18526 [a gammaproteobacterium]) have been isolated and characterized, and both of them use the 2,3-seco pathway to anaerobically degrade androgens. The key intermediate 2,3-seco-androstan-3-oic acid can be used as a signature intermediate for culture-independent environmental investigations of anaerobic degradation of C19 androgens.


Development of public immortal mapping populations, molecular markers and linkage maps for rapid cycling Brassica rapa and B. oleracea.
Publicly available genomic tools help researchers integrate information and make new discoveries. In this paper, we describe the development of immortal mapping populations of rapid cycling, self-compatible lines, molecular markers, and linkage maps for Brassica rapa and B. oleracea and make the data and germplasm available to the Brassica research community. The B. rapa population consists of 160 recombinant inbred (RI) lines derived from the cross of highly inbred lines of rapid cycling and yellow sarson B. rapa. The B. oleracea population consists of 155 double haploid (DH) lines derived from an F1 cross between two DH lines, rapid cycling and broccoli. A total of 120 RFLP probes, 146 SSR markers, and one phenotypic trait (flower color) were used to construct genetic linkage maps for both species. The B. rapa map consists of 224 molecular markers distributed along 10 linkage groups (A1-A10) with a total distance of 1125.3 cM and a marker density of 5.7 cM/marker. The B. oleracea genetic map consists of 279 molecular markers and one phenotypic marker distributed along nine linkage groups (C1-C9) with a total distance of 891.4 cM and a marker density of 3.2 cM/marker. A syntenic analysis with Arabidopsis thaliana identified collinear genomic blocks that are in agreement with previous studies, reinforcing the idea of conserved chromosomal regions across the Brassicaceae.


Trends in seasonal influenza vaccine uptake during pregnancy in Western Australia: Implications for midwives.
Antenatal influenza vaccination is an important public health intervention for preventing serious illness in mothers and newborns, yet uptake remains low. To evaluate trends in seasonal influenza vaccine coverage and identify determinants for vaccination among pregnant women in Western Australia. We conducted an annual telephone survey in a random sample of post-partum women who delivered a baby in Western Australia between 2012 and 2014. Women were asked whether influenza vaccination was recommended and/or received during their most recent pregnancy; women were also asked why or why they were not immunised. Between 2012 and 2014, influenza vaccine coverage increased from 22.9% to 41.4%. Women who reported receiving the majority of their antenatal care from a private obstetrician were significantly more likely to have influenza vaccination recommended to them than those receiving the majority of their care from a public antenatal hospital or general practitioner (p<0.001). In 2014, the most common reason women reported for accepting influenza vaccination was to protect the baby (92.8%) and the most common reason for being unimmunised was lack of a healthcare provider recommendation (48.5%). Antenatal influenza vaccination uptake is increasing, but coverage remains below 50%. A recommendation from the principal care provider is an important predictor of maternal influenza vaccination. Antenatal care providers, including midwives, have a key role in providing appropriate information and evidence-based recommendations to pregnant women to ensure they are making informed decisions. Consistent recommendations from antenatal care providers are critical to improving influenza vaccine coverage in pregnant women.


Dodecyl-TPP Targets Mitochondria and Potently Eradicates Cancer Stem Cells (CSCs): Synergy With FDA-Approved Drugs and Natural Compounds (Vitamin C and Berberine).
Elevated mitochondrial biogenesis and/or metabolism are distinguishing features of cancer cells, as well as Cancer Stem Cells (CSCs), which are involved in tumor initiation, metastatic dissemination, and therapy resistance. In fact, mitochondria-impairing agents can be used to hamper CSCs maintenance and propagation, toward better control of neoplastic disease. Tri-Phenyl-Phosphonium (TPP)-based mitochondrially-targeted compounds are small non-toxic and biologically active molecules that are delivered to and accumulated within the mitochondria of living cells. Therefore, TPP-derivatives may represent potentially "powerful" candidates to block CSCs. Here, we evaluate the metabolic and biological effects induced by the TPP-derivative, termed Dodecyl-TPP (d-TPP) on breast cancer cells. By employing the 3D mammosphere assay in MCF-7 cells, we demonstrate that treatment with d-TPP dose-dependently inhibits the propagation of breast CSCs in suspension. Also, d-TPP targets adherent "bulk" cancer cells, by decreasing MCF-7 cell viability. The analysis of metabolic flux using Seahorse Xfe96 revealed that d-TPP potently inhibits the mitochondrial oxygen consumption rate (OCR), while simultaneously shifting cell metabolism toward glycolysis. Thereafter, we exploited this ATP depletion phenotype and strict metabolic dependency on glycolysis to eradicate the residual glycolytic CSC population, by using additional metabolic stressors. More specifically, we applied a combination strategy based on treatment with d-TPP, in the presence of a selected panel of natural and synthetic compounds, some of which are FDA-approved, that are known to behave as glycolysis (Vitamin C, 2-Deoxy-Glucose) and OXPHOS (Doxycyline, Niclosamide, Berberine) inhibitors. This two-hit scheme effectively decreased CSC propagation, at concentrations of d-TPP toxic only for cancer cells, but not for normal cells, as evidenced using normal human fibroblasts (hTERT-BJ1) as a reference point. Taken together, d-TPP halts CSCs propagation and targets "bulk" cancer cells, without eliciting the relevant undesirable off-target effects in normal cells. These observations pave the way for further exploring the potential of TPP-based derivatives in cancer therapy. Moreover, TPP-based compounds should be investigated for their potential to discriminate between "normal" and "malignant" mitochondria, suggesting that distinct biochemical, and metabolic changes in these organelles could precede specific normal or pathological phenotypes. Lastly, our data validate the manipulation of the energetic machinery as useful tool to eradicate CSCs.


Third party involvement in barroom conflicts.
This study examines the effect of situational variables on whether third parties intervene in conflicts in barroom settings, and whether they are aggressive or not when they intervene. Based on research on bystander intervention in emergencies, we hypothesized that third parties would be most likely to become involved in incidents with features that convey greater danger of serious harm. The situational variables indicative of danger were severity of aggression, whether the aggression was one-sided or mutual, gender, and level of intoxication of the initial participants in the conflict. Analyses consist of cross-tabulations and three-level Hierarchical Logistic Models (with bar, evening, and incidents as levels) for 860 incidents of verbal and physical aggression from 503 nights of observation in 87 large bars and clubs in Toronto, Canada. Third party involvement was more likely during incidents in which: (1) the aggression was more severe; (2) the aggression was mutual (vs. one-sided) aggression; (3) only males (vs. mixed gender) were involved; and (4) participants were more intoxicated. These incident characteristics were stronger predictors of non-aggressive third party involvement than aggressive third party involvement. The findings suggest that third parties are indeed responding to the perceived danger of serious harm. Improving our knowledge about this aspect of aggressive incidents is valuable for developing prevention and intervention approaches designed to reduce aggression in bars and other locations.


Opioid-Sparing Effect of Cannabinoids: A Systematic Review and Meta-Analysis.
Cannabinoids, when co-administered with opioids, may enable reduced opioid doses without loss of analgesic efficacy (ie, an opioid-sparing effect). The aim of this study was to conduct a systematic review to determine the opioid-sparing potential of cannabinoids. Eligible studies included pre-clinical and clinical studies for which the outcome was either analgesia or opioid dose requirements. Clinical studies included controlled studies and case series. We searched Scopus, Cochrane Database of Systematic Reviews, Medline, and Embase. Nineteen pre-clinical and nine clinical studies met the search criteria. Seventeen of the 19 pre-clinical studies provided evidence of synergistic effects from opioid and cannabinoid co-administration. Our meta-analysis of pre-clinical studies indicated that the median effective dose (ED50) of morphine administered in combination with delta-9-tetrahydrocannabinol (delta-9-THC) is 3.6 times lower (95% confidence interval (CI) 1.95, 6.76; n=6) than the ED50 of morphine alone. In addition, the ED50 for codeine administered in combination with delta-9-THC was 9.5 times lower (95% CI 1.6, 57.5, n=2) than the ED50 of codeine alone. One case series (n=3) provided very-low-quality evidence of a reduction in opioid requirements with cannabinoid co-administration. Larger controlled clinical studies showed some clinical benefits of cannabinoids; however, opioid dose changes were rarely reported and mixed findings were observed for analgesia. In summary, pre-clinical studies provide robust evidence of the opioid-sparing effect of cannabinoids, whereas one of the nine clinical studies identified provided very-low-quality evidence of such an effect. Prospective high-quality-controlled clinical trials are required to determine the opioid-sparing effect of cannabinoids.


The ring finger protein 213 gene (Rnf213) contributes to Rift Valley fever resistance in mice.
Rift Valley fever (RVF) is an emerging viral zoonosis that primarily affects ruminants and humans. We have previously shown that wild-derived MBT/Pas mice are highly susceptible to RVF virus and that part of this phenotype is controlled by a locus located on distal Chromosome 11. Using congenic strains, we narrowed down the critical interval to a 530 kb region containing five protein-coding genes among which Rnf213 emerged as a potential candidate. We generated Rnf213-deficient mice by CRISPR/CAS9 on the C57BL/6 J background and showed that they were significantly more susceptible to RVF than control mice, with an average survival time post-infection reduced from 7 to 4 days. The human RNF213 gene had been associated with the cerebrovascular Moyamoya disease (MMD or MYMY) but the inactivation of this gene in the mouse resulted only in mild anomalies of the neovascularization. This study provides the first evidence that the Rnf213 gene may also impact the resistance to infectious diseases such as RVF.


The sss colonization gene of the tomato-Fusarium oxysporum f. sp. radicis-lycopersici biocontrol strain Pseudomonas fluorescens WCS365 can improve root colonization of other wild-type pseudomonas spp.bacteria.
We show that the disease tomato foot and root rot caused by the pathogenic fungus Fusarium oxysporum f. sp. radicis-lycopersici can be controlled by inoculation of seeds with cells of the efficient root colonizer Pseudomonas fluorescens WCS365, indicating that strain WCS365 is a biocontrol strain. The mechanism for disease suppression most likely is induced systemic resistance. P. fluorescens strain WCS365 and P. chlororaphis strain PCL1391, which acts through the production of the antibiotic phenazine-1-carboxamide, were differentially labeled using genes encoding autofluorescent proteins. Inoculation of seeds with a 1:1 mixture of these strains showed that, at the upper part of the root, the two cell types were present as microcolonies of either one or both cell types. Microcolonies at the lower root part were predominantly of one cell type. Mixed inoculation tended to improve biocontrol in comparison with single inoculations. In contrast to what was observed previously for strain PCL1391, mutations in various colonization genes, including sss, did not consistently decrease the biocontrol ability of strain WCS365. Multiple copies of the sss colonization gene in WCS365 improved neither colonization nor biocontrol by this strain. However, introduction of the sss-containing DNA fragment into the poor colonizer P. fluorescens WCS307 and into the good colonizer P. fluorescens F113 increased the competitive tomato root tip colonization ability of the latter strains 16- to 40-fold and 8- to 16-fold, respectively. These results show that improvement of the colonization ability of wild-type Pseudomonas strains by genetic engineering is a realistic goal.